Cochrane Database of Systematic Reviews

Supplementary vitamin E, selenium, cysteine and riboflavin

for preventing kwashiorkor in preschool children in
developing countries (Review)

Odigwe CC, Smedslund G, Ejemot-Nwadiaro RI, Anyanechi CC, Krawinkel MB

Odigwe CC, Smedslund G, Ejemot-Nwadiaro RI, Anyanechi CC, Krawinkel MB.

Supplementary vitamin E, selenium, cysteine and riboflavin for preventing kwashiorkor in preschool children in developing countries.
Cochrane Database of Systematic Reviews 2010, Issue 4. Art. No.: CD008147.
DOI: 10.1002/14651858.CD008147.pub2.

www.cochranelibrary.com

Supplementary vitamin E, selenium, cysteine and riboflavin for preventing kwashiorkor in preschool children in developing countries
(Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Supplementary vitamin E, selenium, cysteine and riboflavin for preventing kwashiorkor in preschool children in developing countries i
(Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]

Supplementary vitamin E, selenium, cysteine and riboflavin

for preventing kwashiorkor in preschool children in developing
countries

Chibuzo C Odigwe1 , Geir Smedslund2 , Regina I Ejemot-Nwadiaro3 , Chiedozie C Anyanechi4 , Michael B Krawinkel5

1 Nigeria Effective Health Care Alliance Programme, Institute of Tropical Disease Research & Prevention, Calabar, Nigeria. 2 Norwegian
Knowledge Centre for the Health Services, Oslo, Norway. 3 Departmentof Public Health, College of Medical Sciences, University of
Calabar, Calabar, Nigeria. 4 Department of Internal Medicine, Federal Medical Centre, Umuahia, Nigeria. 5 Institute of Nutritional
Sciences - International Nutrition, Justus-Liebig-University, Giessen, Germany

Contact address: Chibuzo C Odigwe, Nigeria Effective Health Care Alliance Programme, Institute of Tropical Dis-
ease Research & Prevention, University of Calabar Teaching Hospital, Moore Road, Calabar, Cross River State, Nigeria.
c.odigwe@yahoo.com, codigwe@gmail.com, chibuzo2k2@yahoo.com.

Editorial group: Cochrane Developmental, Psychosocial and Learning Problems Group.

Publication status and date: New, published in Issue 4, 2010.

Citation: Odigwe CC, Smedslund G, Ejemot-Nwadiaro RI, Anyanechi CC, Krawinkel MB. Supplementary vitamin E, selenium,
cysteine and riboflavin for preventing kwashiorkor in preschool children in developing countries. Cochrane Database of Systematic
Reviews 2010, Issue 4. Art. No.: CD008147. DOI: 10.1002/14651858.CD008147.pub2.

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

Background

Protein Energy Malnutrition is an important cause of child morbidity and mortality in middle- and low-income countries. It has been
suggested that excessive free radical activity may be responsible for the clinical manifestation of kwashiorkor. Antioxidants may be able
to curb excessive free radical activity and prevent the development of kwashiorkor in susceptible children.

Objectives

To evaluate the benefits of supplementation of vitamin E, selenium, cysteine and riboflavin (alone or in combination) in preventing
kwashiorkor.

Search methods

We conducted searches of CENTRAL 2009 (The Cochrane Library 2009 Issue 2), MEDLINE 1966 to 2009, EMBASE 1980 to 2009,
CINAHL 1982 to 2009, LILACS 1982 to 2009, Meta register of Controlled trials, Open Sigle, African Index Medicus.

Selection criteria

Randomised controlled trials (RCTs) and quasi-RCTs evaluating vitamin E, selenium, cysteine and riboflavin alone or in combination
in healthy pre-school children in middle- and low-income countries.

Data collection and analysis

Two authors extracted and independently analysed data.

Supplementary vitamin E, selenium, cysteine and riboflavin for preventing kwashiorkor in preschool children in developing countries 1
(Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Main results

One cluster-RCT including 2372 children met our inclusion criteria. Children were randomised, based on household, either to a
supplement containing all four micronutrients or to placebo. No statistically significant difference in the incidence of kwashiorkor
between the intervention and control groups could be demonstrated at 20 weeks (RR 1.70; 95% CI 0.98 to 2.42). Nor could any
statistically significant difference in all-cause mortality be demonstrated (RR 0.75; 95% CI 0.17 to 3.36).

Authors’ conclusions

Based on the one available trial, we could draw no firm conclusion for the effectiveness of supplementary antioxidant micronutrients
for the prevention of kwashiorkor in pre-school children.

PLAIN LANGUAGE SUMMARY

Supplementary vitamin E, selenium, cysteine and riboflavin for preventing kwashiorkor in preschool children in developing
countries

Undernutrition is one of the leading underlying causes of childhood morbidity and mortality in developing countries. Providing
antioxidants that would help curb excess free radicals in the body may help prevent the development of kwashiorkor. We identified one
cluster-RCT that attempted to investigate this. Based on the published evidence reviewed, we could draw no firm conclusions of the
benefits of supplementary antioxidants for the prevention of kwashiorkor in pre-school children. There is a need for further research
in this area to be certain if antioxidant supplementation can help prevent kwashiorkor in young children.

BACKGROUND
Description of the condition
The term kwashiorkor is derived from the Ghanaian word meaning
‘the disease the older child develops when the new child is born’
(Williams 1935). This is because once the next sibling is born the
older child, having lost his or her earlier source of nourishment
in the form of breast milk, has to subsist on a maize gruel alone
that is quite deficient in proteins (Laditan 1999; Williams 1935).
It occurs most frequently in infants and children in developing
countries.
Kwashiorkor is part of a spectrum of diseases collectively referred
to as Protein Energy Malnutrition (PEM). Together with maras-
mus, these diseases form two ends of the disease spectrum of PEM.
These disorders are believed to be a consequence of a coincident
lack of dietary proteins and/or calories in varying proportions
(Laditan 1999). Marasmus is characterised by severe muscle wast-
ing. In marasmus, body weight may be reduced to less than 60%
of the normal weight for that age and it carries a better prognosis
than kwashiorkor. It is also possible for both conditions to overlap,
when it is referred to as marasmic kwashiorkor.
Supplementary vitamin E, selenium, cysteine and riboflavin for preventing kwashiorkor in preschool children in developing countries
(Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Epidemiology
From the earliest clinical descriptions of kwashiorkor (Williams
1935), an association had been established with poverty and so-
cial neglect and the disease is mostly seen in developing countries
(Muller 2005). Globally, it indirectly accounted for 53% of deaths
among children under five between 2000 and 2003, when asso-
ciated with other common childhood diseases like acute respira-
tory infections, diarrhoea, malaria, measles, HIV/AIDS and other
causes of perinatal deaths (Muller 2005).
Although some low- and middle-income countries in Asia are be-
ginning to report a decline in the number of cases of kwashiorkor
diagnosed, the deteriorating socio-economic conditions in others,
especially in certain parts of sub-Saharan Africa, continue to ac-
count for an increase in total disease burden (Sachdev 2000).
Aetiopathogenesis
The commonly acknowledged aetiology for severe PEM is extreme
deficiency of macro-nutrients, i.e. protein and calories (Coward
1979; Waterlow 1984; Laditan 1999). However, the determi-
nant of the clinical presentation along the entire disease spectrum
has been the subject of some controversy and several hypothe-
ses have been put forward to explain the pathogenesis of kwash-
2
iorkor. These include: protein deficiency (Williams 1935), me-
thionine deficiency (Roediger 1995), pellagra (Gillman 1951), di-
etary dysadaptation (Gopalan 1968), cyanogenic glycoside toxic-
ity (Kamalu 1993), aflatoxin poisoning (Hendrickse 1984), ADH-
like effect of free ferritin (Srikantia 1958), inappropriate endocrine
responses (Rao 1974), and free radical damage following excessive
oxidative stress (Golden 1987). With regard to the theory of di-
etary dysadaptation, it is generally believed that kwashiorkor re-
sults from a failure of the body’s compensatory mechanisms for
severe undernutrition, while marasmus represents a compensated
form. The theory of excessive oxidative stress has been proposed
following observations that children with kwashiorkor seemed to
have higher concentrations of biomarkers of oxidative stress when
compared to marasmic children or children who did not have
PEM. It was also found that these children had lower concentra-
tion of antioxidants in their blood. These abnormalities were seen
to revert to normal when they were successfully treated (Golden
1987).
The hypothesis proposed by Golden and Ramdath that kwash-
iorkor results from an imbalance between production and safe dis-
posal of free radicals is the basis for this systematic review. This hy-
pothesis posits that various insults (referred to as noxae in the orig-
inal paper) imposed on the patient produce free radicals, mainly
lipid peroxides and toxic carbonyls. In normal children, the body
is able to handle these radicals and they are dissipated without
causing injury. However, it is believed that in kwashiorkor these
radicals are excessive and so overwhelm the body’s intrinsic dissi-
pation system. This is as a result of the relative/absolute deficiency
of certain components of the dissipation system in the form of
antioxidants (Golden 1987; Golden 1998).
Issues that seem to support this hypothesis include the fact that in-
fection, for example by the measles virus, was found to precipitate
kwashiorkor and the fact that toxins, found to be present in food
due to poor handling and storage, also appeared to be elevated in
kwashiorkor patients. In addition, high iron levels were found in
some of these children. Iron is thought to have a role because it is
able to catalyse reactions that produce free radicals because of the
ease with which it changes valency under redox conditions and
pH. Plasma ferritin has also been demonstrated to be elevated in
these children (Ogon 2006; Sive 1993; Srikantia 1958).
Glutathione, a central component of the protective repertoire by
virtue of its function in helping protect sulfhydryl groups in the
reduced state, is also known to be affected. It has been demon-
strated to be reduced in the red blood cells of children with kwash-
iorkor. Low levels of glutathione have been accounted for by the
fact that most of the body’s store has to be channeled to detoxifica-
tion reactions involving peroxides and carbonyls. Also the enzymes
that function in the reduction of glutathione and reducing equiv-
alent provision, notably glutathione reductase, Glucose-6 Phos-
phate Dehydrogenase and 6- phosphogluconic acid dehydroge-
Supplementary vitamin E, selenium, cysteine and riboflavin for preventing kwashiorkor in preschool children in developing countries
(Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
nase, are induced in kwashiorkor (Golden 1987; Golden 1998;
Jackson 1986; Sive 1993).
Clinical features
Clinically, kwashiorkor produces growth failure, which manifests
itself in deranged anthropometric (body measurement) indices like
weight for age, height for age, and decreased mid upper arm cir-
cumference (MUAC). Other features include generalised oedema,
greatly increased predisposition to infection due to the relative im-
munodeficiency state, anaemia, regression in milestones, skin and
hair changes; the skin lesions commonly associated with kwash-
iorkor include flaky paint dermatoses and fluffiness of the hair.
There is also abdominal swelling, which is accounted for by hep-
atomegaly secondary to fatty infiltration and loss/flabbiness of the
abdominal wall musculature (Laditan 1999; Ogon 2006).
Diagnosis
The Wellcome Working Party classification of protein energy mal-
nutrition specifies the presence of a deranged weight for age value
between 80% and 60% of expected in the presence of oedema
for diagnosis of kwashiorkor (Laditan 1999; Wellcome Working
Party 1970).
Standard treatment
The treatment of kwashiorkor involves nutritional rehabilitation
along guidelines issued by the World Health Organization. This
involves initial hospitalisation and the sequential and systematic
provision of a therapeutic diet with the adequate content of protein
and calories, treatment/correction of electrolyte derangements, hy-
pothermia, hypoglycaemia, dehydration, provision of micronutri-
ents, treatment of infection, psychosocial stimulation and con-
solidation of tissue building nutrition to prevent relapse (World
Health Organization 1999).
Description of the intervention
Vitamin E, selenium, cysteine and riboflavin
This systematic review is interested in appraising the effectiveness
and efficacy of some antioxidants and micronutrient supplements
that may be able to help correct the deficiency that predisposes
susceptible children to kwashiorkor. By susceptible children, we
mean children whose current socio-economic circumstances place
them at risk of becoming malnourished.
We are specifically interested in vitamin E, selenium, cysteine and
riboflavin either singly or delivered in combination prophylacti-
cally to children aged between six months and five years to prevent
kwashiorkor.
3

Vitamin E - also known as alpha tocopherol - is a naturally occur-
ring vitamin whose absorption is facilitated by optimal fat absorp-
tion in the diet. Vitamin E functions as the first line of defence
against polyunsaturated fatty acid peroxidation. It does this by
breaking free radical chain reactions (Murray 2000). The Recom-
mended Daily Allowance (RDA) of vitamin E for children within
the age group of interest in this review is between 4 mg/d and 7
mg/d (Murray 2000; IOM 2000a), with a tolerable upper limit of
1000 IU for adults. At present there is a paucity of data regarding
the precise tolerable upper limit for children within the age group
of interest (IOM 2000a).
Selenium is an integral component of glutathione peroxidase, and
provides defence against hydroperoxides, another source of oxida-
tive stress. It acts synergistically with vitamin E in its action against
lipid peroxidation, which is responsible for some of the destructive
effects of free radicals on cell membranes. Selenium is required in
microgram quantities and is toxic in overdose. Deficiency occurs
in plants and animals raised in areas where soils and drinking wa-
ter have little or no selenium. Healthy populations are known to
consume selenium in the range of 30 mcg/day to 500 mcg/day.
The optimal range for children within the age group of interest in
this review is between 15 mcg/day and 30 mcg/day (IOM 2000a).
The supplement level may be in the range of 100 mcg/day to 200
mcg/day.
Cysteine is a sulphur-containing nonessential amino acid which
is able to bond in a special way to proteins and maintain its struc-
ture in the body. Cysteine is a component of the antioxidant glu-
tathione and can also function in the production of taurine, an-
other amino acid. The body can synthesise cysteine from methio-
nine and other building blocks. Cysteine is rarely used as a dietary
supplement. N-acetyl cysteine (NAC), which contains cysteine, is
more commonly used as a supplement. Cysteine, the amino acid
from which NAC is derived, is found in most high-protein foods
(Murray 2000).
Riboflavin or vitamin B2 is a micronutrient that acts as an integral
component of two coenzymes: flavin adenine dinucleotide (FAD)
and flavin mononucleotide (FMN). A coenzyme is a molecule
required for the activity of another enzyme. These flavin coen-
zymes are critical for the metabolism of carbohydrates, fats, and
proteins into energy. Because riboflavin is an important compo-
nent of these flavin coenzymes, it is thought that riboflavin sup-
plementation can increase the efficiency of energy metabolism in
cells (Murray 2000). FAD and FMN are involved in the activity
of the electron transport chain, an essential component of energy
metabolism. Severe deficiencies in riboflavin can lower levels of
coenzymes, leading to inefficient energy metabolism and conse-
quent energy depletion. Riboflavin is a water-soluble vitamin that
is found naturally in the food we eat. Sources of riboflavin in-
Supplementary vitamin E, selenium, cysteine and riboflavin for preventing kwashiorkor in preschool children in developing countries
(Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
clude organ meats (liver, kidney, and heart) and certain plants such
as almonds, mushrooms, whole grain, soybeans, and green leafy
vegetables (Murray 2000). The Recommended Daily Allowance
(RDA) for the age group of interest in this review is between 0.3
mg/day and 0.6 mg/day (IOM 2000b).
Most of the existing RDA recommendations currently in existence
in the published literature are derived from adult values after taking
into account the results of basic experimental and observational
studies and making adequate statistical adjustments (IOM 1998).
Each of the above micronutrients has some antioxidant effects;
however, it is believed that their antioxidant effects would be
greatly enhanced if they were delivered in combination. This is
because of the nature of the biochemical reactions they catalyse,
which are all interlinked at different metabolic junctions.
How the intervention might work
It is thought that the micronutrients described above may correct
the postulated relative deficiency of antioxidants in children who
are susceptible to kwashiorkor and thereby protect them from
developing kwashiorkor. This hypothesis was first proposed by
Golden and Ramdath (Golden 1982; Golden 1987). Some other
evidence that seems to support this theory includes the observation
of some degree of clinical improvement following administration
of NAC to malnourished children (Manary 2000).
Why it is important to do this review
Malnutrition remains a major problem, particularly for children
living in developing countries. Globally, it indirectly accounted
for 53% of deaths in children under five years old between 2000
and 2003, when associated with other common childhood diseases
like acute respiratory infections, diarrhoea, malaria, measles, HIV/
AIDS and other causes of perinatal deaths (Muller 2005).
There is lack of consensus on the interventions (if any) that can
effectively prevent PEM among these children.
Several interventions like micronutrient supplementation, promo-
tion of breast feeding, food fortification and dietary diversification
have been utilised based on an understanding of the pathogenesis
and pathophysiology of malnutrition, particularly protein energy
malnutrition.
As regards antioxidants and micronutrients, there has been some
speculation that they have a role to play in the pathogenesis of
kwashiorkor. However, the evidence in support of this hypothesis,
that the clinical manifestation of kwashiorkor in the spectrum of
PEM is due to excessive free radical activity and decreased antioxi-
dant ability of the body, is derived mainly from basic experimental
and observational studies. If indeed this theory is correct, there is a
4
need for RCTs, and to enable this to form a strong basis for public
heath practice, there is need for a systematic review of available
evidence as regards the efficacy or otherwise of this intervention
(Becker 1994; Sive 1993) when exploited for purposes of primary
prevention.
OBJECTIVES
To evaluate the effects of supplementation of vitamin E, selenium,
cysteine and riboflavin (alone or in combination) for prevention
of kwashiorkor in pre-school children in low- and middle-income
countries.
METHODS
Criteria for considering studies for this review
Types of studies
RCTs (individual or cluster-randomised).
Quasi-RCTs (where allocation of treatment has been made, for
example, by alternate allocation, date of birth, alphabetical order,
etc).
Types of participants
Healthy children (aged between six months and five years) in com-
munity settings in low- and middle-income countries.
Studies involving children with kwashiorkor and marasmus or any
other chronic illnesses were not eligible.
Types of interventions
Community-based administration for a minimum of four weeks
of a formulation that consists of at least one or more of vitamin E,
selenium, cysteine or riboflavin at doses over and above the RDA.
We included studies if one or more of these micronutrients were
administered, alone or in conjunction with others, but if the dif-
ference between the two groups is only the micronutrients of in-
terest.
By community-based we mean that the intervention is adminis-
tered at home or any other centre designated for its administration
in the community.
Acceptable control conditions include placebo only.
Trials in which at least one of the intervention micronutrients (vi-
tamin E, selenium, cysteine and riboflavin) are provided alongside
other interventions, for example, health education, were eligible
as long as these co-interventions were included in all groups.
Supplementary vitamin E, selenium, cysteine and riboflavin for preventing kwashiorkor in preschool children in developing countries
(Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Types of outcome measures
Primary outcomes
Incidence of kwashiorkor, defined as weight for age less than 80%
of expected with the presence of oedema.
Secondary outcomes
1. Number of children who die from kwashiorkor.
2. Number of children who die from any cause.
3. Kwashiorkor related morbidity e.g. incidence of:
◦ flaky paint dermatoses;
◦ abdominal swelling with hepatomegaly and ascites;
◦ psychomotor retardation.
4. Cognitive development:
◦ intellectual quotient (because chronic malnutrition
adversely affects cognitive development).
5. Hospitalisation: incidence and duration (for kwashiorkor).
6. Adverse events.
7. Economic data if available.
Timing of outcome assessment
Depending on availability of data, we planned to report our out-
comes as short term (one month); medium term (six months); and
long term (one year).
Search methods for identification of studies
Electronic searches
We searched the Cochrane Central Register of Controlled Trials,
(CENTRAL) (The Cochrane Library 2009, Issue 2); MEDLINE
1955 to May 2009; EMBASE 1980 to 2009 week 20; CINAHL
1982 to May 2009; LILACS 1982 to May 2009; MetaRegister of
Controlled Trials, (for ongoing trials), searched May 2009; Disser-
tation Abstracts searched May 2009; OpenSigle, (for grey litera-
ture), searched May 2009; and the African Index Medicus searched
May 2009. The search strategies used to search these databases can
be found in the following appendices:
CENTRAL Appendix 1, MEDLINE Appendix 2, EMBASE Ap-
pendix 3, CINAHL Appendix 4, LILACS Appendix 5, MetaReg-
ister of Controlled Trials, (ongoing trials), and Dissertation Ab-
stracts Appendix 6, OpenSigle (grey literature) Appendix 7,
African Index Medicus Appendix 8.
We did not use an RCT filter in order to obtain as many related
studies as possible. We also searched the reference lists of studies
that met our inclusion criteria. We applied no language or date
restrictions.
5
Searching other resources
We searched conference proceedings (conferences of paediatric and
nutrition organisations held within the last decade), and contacted
researchers, organisations, and pharmaceutical companies in the
area by email.
We scanned references of retrieved articles and relevant reviews
for potentially eligible studies. We contacted authors of included
trials by email or post asking for help in clarifying relevant and
missing data and to identify reports of unpublished or ongoing
trials. We planned to make up to two different contact attempts per
identified author (e-mail and post). We also anticipated that a great
deal of relevant literature may be unpublished, or published only
as in-house reports, and attempted to make contact by email or
letter with relevant NGOs and experts in the field to locate reports
of unpublished or ongoing studies. We contacted the following
organisations: World Health Organization, World Bank, United
Nations Children’s Fund, World Food Programme, International
Food Policy Research Institute (IFPRI), Famine Early Warning
System (FEWS), The Centre for the Study of African Economies,
the Institute for Agriculture and Trade Policy, InterAction.org,
Oxfam, Médecins sans Frontières, DFID, UK and USAID. We
were interested in information generated within the last five years
as regards the websites.
We searched Clinical Trials.Gov and the WHO Clinical Trials
platform to enable us to obtain information regarding ongoing
trials, and also to obtain information regarding completed but
unpublished trials.
We also identified experts in the field and enquired about ongoing
or completed trials. We identified from the author line of retrieved
papers, conference proceedings, and websites of leading universi-
ties and research centres.
We attempted to identify all relevant trials regardless of language
or publication status (published, unpublished, in press, and in
progress).
Data collection and analysis
Selection of studies
Two authors (Odigwe and Anyanechi) independently assessed ti-
tles and abstracts of articles identified in the search to determine
whether they met the inclusion criteria or not. We also checked
the reference lists of all retrieved publications to search for relevant
studies. We carefully assessed abstracts of retrieved studies and re-
trieved those with potential in full and checked them against our
eligibility criteria.
A data extraction form was developed for this purpose. The two
authors who applied the inclusion criteria were not blinded to the
names of the authors, institutions or journal of publication. We
planned that in situations where there were differences of opinion
regarding suitability for inclusion, that we would have resolved
Supplementary vitamin E, selenium, cysteine and riboflavin for preventing kwashiorkor in preschool children in developing countries
(Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
this by discussion. We would have resolved any doubt during this
process by consultation with a third reviewer (Ejemot Nwadiaro or
Geir Smedslund) or through discussion with the editorial base. If
necessary, we would have sought further information from trialists.
Data extraction and management
Two authors (Odigwe and Smedslund) independently extracted
data and recorded the following data on data extraction forms:
identification details of the study; method of random allocation to
intervention/control groups; details about participants including
baseline nutrition status; description and length of the interven-
tion; the primary and secondary outcome measures and any in-
formation pertaining to adverse events. We also extracted data on
risk of bias issues, namely method of allocation sequence genera-
tion, allocation concealment, blinding, incomplete outcome data,
selective outcome reporting and issues regarding the funding of
the study and source of ethical approval. We also extracted data
on the results and effects of treatment. We had planned to resolve
any disagreement between the reviewers by discussion and by con-
sultation with a third reviewer (Ejemot Nwadiaro or Anyanechi),
with input from the editorial base.
One author (Odigwe) entered data into Review Manager (RevMan
2008) and a second author (Smedslund) checked data.
Assessment of risk of bias in included studies
Two review authors independently assessed methodological qual-
ity according to the specifications of the latest edition of the
Cochrane Handbook for Systematic Reviews of Interventions (Higgins
2008). Review authors independently assessed the risk of bias
within each included study in relation to the following five do-
mains with ratings of ’yes’ (low risk of bias); ’no’ (high risk of bias);
and ’unclear’ (uncertain risk of bias).
Sequence generation
For allocation sequence generation, low risk of bias refers to the fact
that allocation sequence was generated by a method that would
completely ensure that only chance would determine to which
group a patient would belong. An example of a low risk of bias
method for generating allocation sequence would be the use of a
table of random numbers or the use of a computer random number
generator.
Description: the method used to generate the allocation sequence
was described in detail so as to assess whether it should have pro-
duced comparable groups; review authors’ judged: was the alloca-
tion sequence adequately generated?
We rated as follows: ’yes’ (low risk of bias); ’no’ (high risk of bias);
and ’unclear’ (uncertain risk of bias).
6
Allocation concealment
For allocation concealment, low risk of bias refers to the fact that
the trialists made a concerted effort to ensure that at the time at
which the decision was made to include trial participants in the
trial and allocate them to either intervention or control groups,
the trialist allocating them to these groups is completely unaware
of the treatment the participant would receive in that group. An
example of this would be the use of sealed opaque envelopes to
conceal allocation.
Description: was the method used to conceal the allocation se-
quence described in sufficient detail to assess whether interven-
tion schedules could have been foreseen in advance of, or during,
recruitment? Based upon this, review authors judged whether al-
location was adequately concealed?
We rated as follows: ’yes’ (low risk of bias); ’no’ (high risk of bias);
and ’unclear’ (uncertain risk of bias).
Blinding
For blinding, low risk of bias refers to the fact that a concerted effort
is made to ensure that the outcome assessor and the trial participant
are unaware of the treatment which they have received. For the
sort of trials that would be included in this review, this could be
achieved by the use of a matching placebo and the administration
of the study medication by other trial staff not involved with the
outcome assessment.
Description: were any measures used to blind participants, per-
sonnel and outcome assessors described so as to assess knowledge
of any group as to which intervention a given participant might
have received? Based upon this, review authors judged whether
knowledge of the allocated intervention was adequately prevented
during the study?
We rated as follows: ’yes’ (low risk of bias); ’no’ (high risk of bias);
and ’unclear’ (uncertain risk of bias).
Incomplete outcome data
Description: in instances where studies did not report complete
outcome data, we attempted to obtain missing data by contacting
the study authors. We extracted and reported on data on attrition
and exclusions as well as the numbers involved (compared with
total randomised), reasons for attrition/exclusion where reported
or obtained from investigators, and any re-inclusions in analyses
performed by review authors. Based upon this, review authors
judged whether the researchers dealt with incomplete data. (See
also ’Dealing with missing data’, below.)
We rated as follows: ’yes’ (low risk of bias); ’no’ (high risk of bias);
and ’unclear’ (uncertain risk of bias).
Selective outcome reporting
Description: we attempted to assess the possibility of selective out-
come reporting by investigators; based upon this, review authors
Supplementary vitamin E, selenium, cysteine and riboflavin for preventing kwashiorkor in preschool children in developing countries
(Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
judged whether reports of the study were free from suggestion of
selective outcome reporting.
We rated as follows: ’yes’ (low risk of bias); ’no’ (high risk of bias);
and ’unclear’ (uncertain risk of bias)
We explored other sources of bias, particularly the sources of fund-
ing of the included studies and other study peculiarities.
Measures of treatment effect
Continuous data
We analysed continuous data where means and standard devia-
tions were available and there was no clear evidence of skew in
the distribution. If mean difference was provided, we planned to
extract and utilise this for the analysis irrespective of provision of
mean and standard deviation. We were interested in the change of
data from the baseline.
Binary data
We analysed binary outcomes by calculating the relative risk with
95% confidence intervals.
Unit of analysis issues
Cluster-RCTs
Statistical methods for cluster-RCTs used in the review are those
that are described in the Cochrane Handbook for Systematic Reviews
of Interventions (Higgins 2008).
We planned to meta-analyse all the studies together, or at least
combine all the cluster-RCTs, if possible. We anticipated that we
may be able to do this if the outcomes of interest in the cluster-
RCTs were not correctly adjusted for clustering.
We planned to re-analyse, if possible, studies judged not to have
been analysed by adjusting for clustering. We planned to extract
data that would enable a re-analysis. We planned to collect data on
the number of clusters (or groups) randomised to each interven-
tion group; or the average (mean) size of each cluster, and also the
outcome data ignoring the cluster design for the total number of
individuals. We also planned to collect data regarding the estimate
of the intracluster (or intraclass) correlation coefficient (ICC). In
the event of this not being reported, we planned to obtain this
from a reliable external source. We planned to contact the trial-
ists to provide missing information that would enable us do this.
However the included trial was reported in such a way that we did
not need to do this.
We also sought the help of statisticians from the Developmental
and Psychosocial Learning Problems Review Group to ensure that
appropriate methods were utilised.
7
Dealing with missing data
When necessary, we planned to contact the study author(s) to sup-
ply any unreported data (for example, group means and standard
deviations (SDs), details of dropouts, and details of interventions
received by the control group). If a study reported outcomes only
for participants completing the trial or only for participants who
followed the protocol, we planned to contact the authors and ask
them to provide additional information to facilitate an intention-
to-treat analyses.
Assessment of heterogeneity
We assessed important clinical heterogeneity by comparing the
distribution of important clinical heterogeneity factors (study par-
ticipants, study setting, type of intervention and co-intervention)
and methodological heterogeneity factors (randomisation, alloca-
tion concealment, blinding of outcome assessment, losses to fol-
low up).
We assessed statistical heterogeneity by examining I2 (Higgins
2002), a quantity which describes approximately the proportion
of total variation in effect estimates that is due to true variation in
effects between studies. In addition, we planned to employ a Chi2
test of homogeneity to determine the strength of evidence against
the hypothesis that all studies have the same underlying effect size.
Assessment of reporting biases
We planned to draw funnel plots (estimated treatment effects
against their standard error). Asymmetry could be due to publica-
tion bias, but could also be due to a relationship between trial size
and effect size (Egger 1997).
Selective outcome reporting
We addressed the issue of selective outcome reporting by internal
evidence within published studies as we could not check the pro-
tocols of included studies.
Data synthesis
Where the interventions were the same or similar enough, we
planned to synthesise results in a meta-analysis where there was
no important clinical heterogeneity.
We planned that studies that investigated the impact of single
micronutrient intervention agents would be combined only with
other studies of the same micronutrient.
We planned to combine trials that contained two or more mi-
cronutrients with trials that contain at least two of the same mi-
cronutrients.
If continuous outcomes were measured identically across studies,
we planned to calculate an overall mean difference and 95% con-
fidence interval (CI). If the same continuous outcome was mea-
Supplementary vitamin E, selenium, cysteine and riboflavin for preventing kwashiorkor in preschool children in developing countries
(Review)
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sured differently across studies, we planned to calculate an overall
standardised mean difference (SMD) and 95% CI.
We planned to include studies with skewed data into the review
but not to meta-analyse them with the data from other studies.
We planned to present these data separately.
If some primary studies report an outcome as a dichotomous mea-
sure and others use a continuous measure of the same construct, we
planned to conduct separate meta-analyses (one for relative risks
and another for MD/SMDs); thereafter we would introduce a cut-
off (with specific rationale) to enable conversion from continuous
to dichotomous and conduct another analysis; thirdly, we would
convert effect magnitudes from continuous to dichotomous and
re-analyse. We planned to discuss any major differences in results,
and attempt to explain the reason for the differences (Higgins
2003).
We planned to investigate heterogeneity using I2 and would use
a random-effects model for meta-analysis, even when I2 was less
than 25%. If I2 was greater than 25% we still planned to conduct
a random-effects meta-analysis. If, however, I2 was greater than
50%, we planned to explore the reasons and decide whether it was
appropriate to undertake a meta-analysis.
We would have considered interventions similar if the same mi-
cronutrients were administered (chemically the same and possess-
ing similar biologic activity profile) and if the administered dose
was within the supplement range, or above the recommended daily
requirement for the children within the age group of interest.
Subgroup analysis and investigation of heterogeneity
Depending on the data reported in the included studies, we
planned to conduct the following subgroup analyses:
1. the differential impact of studies including children
younger than 24 months and those older than 24 months;
2. the differential impact of baseline nutrition status, the
incidence of kwashiorkor developing in underweight versus
normal weight for age children prior to randomisation;
3. the differential impact of different micronutrient
combinations versus placebo;
4. the differential impact of single micronutrient
administration versus combined administration.
Sensitivity analysis
We planned to perform sensitivity analyses to explore the influence
of adequate allocation concealment and studies where a significant
number of the participants were lost to follow up.
RESULTS
8
Description of studies
Results of the search
We conducted the search for relevant studies for inclusion in the
review (see Appendices 1-8 for full details of the search terms and
databases searched) on 21 May 2009. The search yielded a total
of 164 records after duplicate records were removed using ProCite
Reference Manager Software.
Two authors (CO and CA) checked the title and abstract of all
records, and identified a total of 11 studies for more detailed con-
sideration. Of these, we deemed only one trial eligible for inclu-
sion (Ciliberto 2005). Two authors (CO and GS) independently
extracted data and another author (CA) subsequently compared/
verified from the trial report.
Included studies
Ciliberto 2005 was a double blind placebo controlled cluster-ran-
domised trial that evaluated the efficacy of an antioxidant cocktail
of all the four micronutrient supplements of interest. The trial was
conducted in Malawi. The total trial duration was five months.
The study participants were 2372 children from 2156 households
aged between 12 and 48 months.
Healthy children were randomised by household to either receive
the intervention or placebo. The intervention consisted of daily
administration of a citrus flavoured powder containing riboflavin,
vitamin E (alpha tocopherol), selenium and NAC. The placebo
consisted of a similar-tasting powder with no active ingredient.
The children in both groups were to drink the powder daily for
20 weeks, which was the entire trial duration. Follow up was con-
ducted at two-weekly intervals. The researchers assessed the partic-
Supplementary vitamin E, selenium, cysteine and riboflavin for preventing kwashiorkor in preschool children in developing countries
(Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ipants for the development of oedema, the primary outcome mea-
sure of the trial. This trial reported data for only three outcomes
of interest in the review - incidence of kwashiorkor, incidence of
hospitalisation and all-cause mortality.
Incidence of kwashiorkor was 3.29% in the intervention group
and 1.93% in the control group. Three deaths due to all causes
were reported in the intervention group and four in the control
group. One of our secondary outcomes was the incidence of hos-
pitalisation; two children were hospitalised, but no information
was given as to which group they belonged. The trial did not re-
port any data with regard to cause-specific mortality, incidence
of other kwashiorkor-related morbidity like flaky paint dermato-
sis, abdominal swelling and ascites, psychomotor retardation, and
cognitive indices. No economic data were reported. No adverse
events (moderate or severe) were reported. See the ’Characteristics
of included studies’ table.
Excluded studies
We excluded the studies in question mainly because they did not
address the review question with regard to prevention of kwash-
iorkor or were not randomised trials. Of the 11 studies that we
closely scrutinised, we ultimately excluded 10 for one or both of
these reasons. Because these studies did not address the review
question we have not provided any further information on them.
We identified no ongoing studies that would meet the inclusion
criteria for this review.
Risk of bias in included studies
Figure 1
9
 Figure 1. Methodological quality summary: review authors’ judgements about each methodological quality
item for each included study.

Allocation
1. Sequence generation
Allocation sequence for the included trial was reported as gener-
ated by a computerised random number generator. Siblings re-
ceived data cards with the same letter of allocation, as the unit of
randomisation was the household and not the individual child.
This method of generating an allocation sequence is likely to pro-
duce similar groups at baseline and we consider it adequate. There-
fore we have listed the risk of bias as low.
2. Allocation concealment
The trial report clearly stated that all investigators and the caretak-
ers of the participants were blind as to which letters (of allocation)
were placebo and which contained antioxidants. However, they
do not explicitly state the method used to conceal the allocation.
We are therefore unable to judge the appropriateness or otherwise
and have rated this as an unclear risk of bias.
Blinding
None of the children, investigators or child caretakers knew to
which group a child belonged (either placebo or active powder).
We have rated this as having a low risk of bias.
Incomplete outcome data
This study reported 40 children as lost to follow up. This translates
to an attrition rate of 1.7%. We have rated this as a low risk of
bias.
Selective reporting
We were not able to compare the study report with the protocol,
but have no reason to believe the trial report is biased by selective
outcome reporting after an appraisal of the study report. However,
because we are not able to exhaustively investigate this, we would
rate this as an unclear risk of bias
Other potential sources of bias
Funding for the study was obtained from the United States Depart-
ment of Agriculture/Agricultural Research Service and the Allen
Foundation, and the investigators did not report any conflicts of

Supplementary vitamin E, selenium, cysteine and riboflavin for preventing kwashiorkor in preschool children in developing countries 10
(Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
interest. Furthermore, the sponsors had no role in the design, con-
duct or reporting of the study.
We also examined the trial report for particular issues that could
bias a cluster-randomised trial, namely recruitment bias, baseline
imbalance, loss of a whole cluster, and statistical analysis allowing
for the cluster design (although they do not explicitly report an
intracluster correlation coefficient). We have not identified any
other issues that could potentially bias the study.
Effects of interventions
Primary outcome
Effect of a combination of vitamin E, selenium cysteine and riboflavin
on incidence of kwashiorkor
Data reported in the one included trial (Ciliberto 2005) showed no
statistically significant difference in the incidence of kwashiorkor
between the intervention and control groups at 20 weeks (RR 1.70;
95% CI 0.98 to 2.42 using a statistical technique that adjusted for
the clustering effect). There was a tendency to a higher incidence
in the intervention group (39 children out of 1184 randomised
developed kwashiorkor) than in the control group (23 children out
of 1188), although this difference was not statistically significant.
The confidence interval reported in the table and meta-analysis
figure has not taken into consideration the fact that the reported
data were from a cluster randomised trial. Our review is based on
the confidence interval we have reported above, which has taken
this fact into consideration.
We have found no studies which investigated the effect of indi-
vidual micronutrient supplements.
Secondary outcomes
Kwashiorkor specific mortality
The study reported no data with regard to cause specific mortality.
All cause mortality
The study reported data on the effect of the intervention on all-
cause mortality, which although different for the two groups (three
children in intervention group versus four children in control
group) as not clinically or statistically significant in either case.
Incidence and duration of hospitalisation due to kwashiorkor
A report regarding the incidence of hospitalisation among the trial
participants was made (two children were hospitalised), although
this was not broken down into the groups to which they had been
randomised.
Other kwashiorkor related morbidity
The study reported no data on the effects of the intervention on
the other outcomes we were interested in, namely kwashiorkor
related morbidity (incidence of flaky paint dermatosis, incidence
of abdominal swelling and ascites, incidence of psychomotor re-
tardation).
Adverse events
Supplementary vitamin E, selenium, cysteine and riboflavin for preventing kwashiorkor in preschool children in developing countries
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There were no reported moderate or severe adverse events in either
groups.
Economic data
There were no reports of economic data.
DISCUSSION
Summary of main results
This review has found that at present the administration of an-
tioxidant supplements for the primary prevention of kwashiorkor
at best has no effect on the incidence of kwashiorkor and all cause
mortality.
Overall completeness and applicability of
evidence
We are unable to draw any conclusions at this time regarding
the applicability or otherwise of this intervention because of the
general paucity of evidence from RCT that have attempted to
answer this question with which the methods and findings of this
trial could be compared.
The question as to the role of excessive free radical activity in the
pathogenesis of kwashiorkor is one that has generated a great deal
of debate over the last 20 years. More important to stakeholders
in middle and low income countries is the question about the po-
tential applicability of this knowledge in the design of an effective
prevention strategy that could be applied on a massive scale in
middle- and low-income countries, particularly the countries of
sub-Saharan Africa.
This review sought to verify the existence of RCT evidence with
respect to this issue and to ascertain the direction and strength of
this evidence.
Quality of the evidence
Despite an extensive search for both published and unpublished
evidence, we only identified and have reported evidence from one
large cluster RCT (Ciliberto 2005) with a low risk of bias which
attempted to answer this question. This trial randomised 2372
children from 2156 households to receive either a supplement
powder containing Vitamin E, selenium, cysteine and riboflavin
at a dose well above their recommended dietary requirement or a
matched placebo and had the development of kwashiorkor as its
main outcome. This trial did not find any statistically significant
difference between the incidence of kwashiorkor between the two
groups at 20 weeks of follow up. It also did not demonstrate any
beneficial effect on all-cause mortality.
11
Potential biases in the review process
Our review sought any form of randomised trial evidence.We did
not find and have not excluded any trials that may have appeared to
attempt to answer our review question. We embarked on an exten-
sive search and actually sought the help of individual researchers,
funding institutions and research organisations active in the field
of malnutrition.
Agreements and disagreements with other
studies or reviews
In the light of our findings, the question also remains to be an-
swered if similar supplements could have any clinically beneficial
role in the treatment of kwashiorkor. This would still be a rel-
evant question both from the fact that the observational studies
that paved the way for the hypothesis of excessive oxidative stress
were actually in ill children and also from the point of view that a
proof of effectiveness would allow better use of resources towards
case management rather than prevention. In the light of this re-
view, one may think that it may also be worthwhile to re-examine
the issue that the low levels of antioxidants observed in the earlier
studies may be a consequence rather than a cause of kwashiorkor.
To the best of our knowledge, no other systematic review has
attempted to answer our research question and so we are unable
to comment on the aspects of our review that may have agreed or
disagreed with their findings.
AUTHORS’ CONCLUSIONS
Implications for practice
There is as yet insufficient evidence to support the use of micronu-
trient supplementation, particularly antioxidant micronutrients,
REFERENCES
References to studies included in this review
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Becker 1994
Becker K, Bötticher D, Leichsenring M. Antioxidant
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as a tool for prevention of kwashiorkor in susceptible children.
Implications for research
There is a need for other large, well conducted and reported studies
that would attempt to assess the effects of antioxidant micronu-
trients in the primary prevention of kwashiorkor with a view to
establishing the existence of a benefit or otherwise of this interven-
tion. The trials should also include some cost effectiveness analy-
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enough to demonstrate any clinically meaningful effect, future tri-
als could still consider a longer duration of follow up, as this would
in any case either throw up an existing effect which is as yet un-
detectable or further buttress the fact that indeed no meaningful
effect exists.
ACKNOWLEDGEMENTS
We would like to thank Professor Mike Clarke, Professor of Clin-
ical Epidemiology, University of Oxford and Director of the UK
Cochrane Centre, Drs Phil Wiffen, Anne Eisinga, Carol Lefebvre
and Sally Hopewell of the UK Cochrane Centre/University of Ox-
ford for their help with the protocol preparation and the conduct
of the review.
We are grateful to Professor Martin Meremikwu, Consultant Pae-
diatrician and Professor Clement Odigwe, Consultant Physician,
both of the University of Calabar Teaching Hospital, Calabar,
Nigeria for their kind and constructive comments during the
preparation of the review.
We are very grateful to Professor Geraldine Macdonald, Jo Abbott
and Chris Champion of the CDPLPG Editorial Base. Our sincere
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∗
Indicates the major publication for the study

Supplementary vitamin E, selenium, cysteine and riboflavin for preventing kwashiorkor in preschool children in developing countries 14
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CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]

Ciliberto 2005

Methods Cluster RCT conducted in 8 villages in an area of rural Malawi with a high incidence
of kwashiorkor. Unit of randomisation was the household. Trial was conducted for 5
months between November 2003 and March 2004, and follow up was for 20 weeks
Computer generated randomisation.
Investigators and caregivers were blinded to allocation.
20 week follow up.

Participants 2372 healthy children aged between 12 and 48 months from 2156 Households. Mean
ages were 28.2 and 28.5 months in intervention and control groups respectively. Indices
of baseline nutrition status were mean and standard deviation of the weight for age in z-
scores of the participants (-1.4 and 1.0 respectively in both groups); and the mean and
standard deviation of the circumference of middle upper arm in centimetres (14.8 and
1.3 respectively in both groups)
Exclusion criteria were the presence of severe chronic illness and oedema at the time of
enrolment

Interventions INTERVENTION GROUP: The intervention consisted of daily administration of a

citrus flavoured powder containing 1.8 mg of riboflavin, 23 mg of vitamin E (alpha
tocopherol), 55 mcg of selenium and 300 mg of N acetyl cysteine. Intervention was
administered at home by the caregiver
CONTROL GROUP: The placebo consisted of a similar tasting powder with no active
ingredient. The children in both groups were to drink the powder daily for 20 weeks
which was the entire trial duration
Follow up was conducted at two-weekly intervals in the community by a study team
comprising two investigators and two study nurses

Outcomes Participants were assessed for the development of oedema by compressing the skin over
both of the child’s fourth metatarsal bones with a firm finger for 10 seconds; and looking
for evidence of pitting. Development of oedema was the primary outcome measure of
the trial. Secondary outcomes were:
• number of deaths due to any cause;
• rate of change in weight;
• gain in circumference of the mid upper arm and length of the arm;
• number of days of fever, cough and diarrhoea.

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Adequate sequence generation? Low risk Allocation sequence for the included trial
was generated by a computerised ran-

Supplementary vitamin E, selenium, cysteine and riboflavin for preventing kwashiorkor in preschool children in developing countries 15
(Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Ciliberto 2005 (Continued)

dom number generator blocked in groups

of 200. These numbers were noted on
the cards with which children were ran-
domised. Siblings received data cards with
the same letter of allocation as the unit was
the household and not the individual child

Allocation concealment? Unclear risk It was clearly stated that all investigators
and the caretakers of the participants were
blind as to which letters (of allocation)
were placebo and which contained antiox-
idants. The authors do not explicitly state
the method used to conceal the allocation

Blinding? Low risk All the investigators (who assessed the out-
All outcomes comes) and child caretakers were blinded
as to the content of the allocation (either
placebo or active powder) each child had
received

Incomplete outcome data addressed? Low risk 40 children were reported to have been lost
All outcomes to follow up. The main reasons for this,
where it was known, were family moving
from trial location, child not liking the
taste of the intervention and carer unable to
bring the child for follow up. The reasons
were similar in both groups and the number
of losses were similar in both groups, both
in terms of the clusters and individual chil-
dren. The authors reported performing an
intention-to-treat analysis of the data. They
reported outcomes for all the randomised
participants in the groups to which they
were randomised and measured outcome
data in all participants up to the end of the
study for most of the participants and up
to the last follow up for those who died or
were lost to follow up

Free of selective reporting?
Unclear risk We were not able to compare the study re-
port with the protocol but have no reason
to believe the trial report is biased by selec-
tive outcome reporting after an appraisal of
the study report. However, because we are
not able to exhaustively investigate this, we
would rate this as an unclear risk of bias

Free of other bias? Low risk We identified no particular issues that

could bias a cluster RCT namely recruit-
ment bias, baseline imbalance, loss of a

Supplementary vitamin E, selenium, cysteine and riboflavin for preventing kwashiorkor in preschool children in developing countries 16
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Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Ciliberto 2005 (Continued)

whole cluster and statistical analysis allow-

ing for the cluster design

Supplementary vitamin E, selenium, cysteine and riboflavin for preventing kwashiorkor in preschool children in developing countries 17
(Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DATA AND ANALYSES

Comparison 1. Supplements versus placebo

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Incidence of kwashiorkor 1 2372 Risk Ratio (M-H, Random, 95% CI) 1.70 [1.02, 2.83]
2 Number of deaths due to any 1 2372 Risk Ratio (M-H, Random, 95% CI) 0.75 [0.17, 3.36]
cause

CONTRIBUTIONS OF AUTHORS
Chibuzo Odigwe conceived the review question and wrote the protocol with assistance from Drs Chiedozie Anyanechi, Geir Smedslund,
Regina Ejemot-Nwadiaro and Professor Michael Krawinkel.
Professor Geraldine Macdonald and Dr Jane Dennis provided assistance from the Cochrane Developmental Psychosocial and Learning
Problems Group editorial base.
Drs Phil Wiffen and Sally Hopewell from the UK Cochrane Centre provided methodological support.
Jo Abbott (TSC, CDPLPG) and Anne Eisinga (Information Specialist, UK Cochrane Centre) ran the searches, and Chibuzo Odigwe
and Chiedozie Anyanechi vetted the results in pairs.
Chibuzo Odigwe assessed studies for eligibility, extracted data and entered into RevMan 5.0 in pairs Geir Smedslund, Chiedozie
Anyanechi and Regina Ejemot Nwadiaro checked data entry. Chibuzo Odigwe and Geir Smedslund wrote the final review with
contribution from all the authors.

DECLARATIONS OF INTEREST
None known.

SOURCES OF SUPPORT

Internal sources
• Insitute of Tropical Disease Research and Prevention, University of Calabar Teaching Hospital, Nigeria.
IT and Logistics Support
• College of Medical Sciences, University of Calabar, Nigeria.
Logistics support
• Federal Medical Centre, Umuahia, Nigeria.
Logistics Support
• Norweigian Knowledge Centre for the Health Services, Oslo, Norway.
• Justus Liebig University, Giessen, Germany.

Supplementary vitamin E, selenium, cysteine and riboflavin for preventing kwashiorkor in preschool children in developing countries 18
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Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
External sources
• UK Cochrane Centre, Oxford, UK.
Mentorship, Training, IT, and Logistics
• Aubrey Sheiham Public Health and Primary Care Scholarship, UK.

INDEX TERMS

Medical Subject Headings (MeSH)

Antioxidants [∗ administration & dosage]; Cysteine [∗ administration & dosage]; Kwashiorkor [∗ prevention & control]; Micronutrients
[administration & dosage]; Riboflavin [∗ administration & dosage]; Selenium [∗ administration & dosage]; Vitamin E [∗ administration
& dosage]

MeSH check words

Child, Preschool; Humans; Infant

Supplementary vitamin E, selenium, cysteine and riboflavin for preventing kwashiorkor in preschool children in developing countries 19
(Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.